tbuckley/cabot-search huggingface dataset:
Comparing rate of immunotherapy treatment change due to toxicity by gender.
Authors: Kevin Joseph Chua, Joshua Sterling, Sai Krishnaraya Doppalapudi, Alain Kaldany, Shane Kronstedt, Arnav Srivastava, Hao Liu, Eric A. Singer
Journal: Journal of Clinical Oncology (2022)

2656 Background: Immunotherapy (IO) is associated with a variety of treatment related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females Methods: The Oncology Research Information Exchange Network (ORIEN) Avatar Database collects clinical data from ten different United States cancer centers, where patients receive IO. Of 1,035 patients receiving IO, 447 patients were analyzed, excluding those (N = 573) who did not have documentation noting if a patient changed treatment. 15 additional patients with an unknown or gender-specific cancer were excluded. All cancer types and stages were included. Primary endpoint was documented treatment change due to toxicity. Significance was calculated with logistic regression, linear regression, chi-squared test for categorical variables and Mann-Whitney U test for continuous nonparametric variables. Results: 447 patients (281 males and 166 females) received IO treatment for cancer. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course compared to males on Mann-Whitney U test (median 3.7 vs 5.1 months, respectively, p=0.02) and multivariable linear regression (Beta -3.87, 95% CI -6.591, -1.149, p=0.005). 54 patients changed IO treatment due to toxicity. There was no significant difference in the rate of treatment change due to toxicity between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and logistic regression (Table). Pembrolizumab, Nivolumab, Ipilimumab/Nivolumab, Ipilimumab, Durvalumab, Avelumab, and Atezolizumab were given to 16, 14, 9, 9, 3, 2 and 1 patients who changed treatment due to toxicity, respectively. The median length of time for IO treatment prior to change for toxicity was 3 months (IQR 1.4 – 5.9 months). Significantly more patients with COPD changed treatment due to toxicity (Table). Conclusions: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity related treatment change was associated with COPD. Studies with larger sample sizes with more granular data (i.e., type of adverse effects) are needed to truly characterize if a difference between genders and IO toxicity exists. [Table: see text]
Association between unmet needs and utilization of emergency services among cancer survivors in Canada.
Authors: Megan E Delisle, Amirrtha Srikanthan, Ying Wang, Margaret I Fitch
Journal: Journal of Clinical Oncology (2022)

12131 Background: In 2016, the Canadian Partnership Against Cancer distributed surveys to over 40,000 cancer survivors to understand their experiences transitioning from primary cancer treatment to follow-up cancer care. Previously reported results of this survey identified that cancer survivors had high rates of unmet physical, emotional and practical needs. This study describes the association between these unmet needs and emergency services (ES) utilization within the first three years after cancer treatment. Methods: 13,319 respondents returned the survey (response rate 33%). Respondents in this study have non-metastatic breast, hematologic, colorectal, melanoma or prostate cancer. The association between self-reported unmet needs and ES utilization was assessed using multivariable logistic regression. High ES utilization was defined as accessing ES more than three times per year during the first three years after active cancer treatment. Results: 8,911 participants are included in this analysis; 80.5% reported at least one unmet practical, physical, and emotional need (n=7169, Table). A total of 3.9% (n=344) reported high ES utilization. Unmet needs were a significant predictor of high ES utilization (OR 1.75 95% CI 1.14-2.68 p=0.01). Other significant predictors of high ES utilization on the multivariable analysis included: not being able to identify a healthcare provider in charge of follow-up cancer care (OR 2.73 95% CI 1.32-5.65 p=0.01), high oncologist utilization (OR 3.08 95% CI 2.28-4.15 p&lt;0.01), high primary care provider utilization (OR 2.3 95% CI 1.76-3.0 p&lt;0.01), having a chronic condition (OR 1.6 95% CI 1.19-2.07 p&lt;0.01), having colorectal cancer (OR 2.12 95% CI 1.31-3.44 p&lt;0.01), being enrolled in a clinical trial (OR 1.54 95% CI 1.11-2.16 p=0.01), and rating follow-up cancer care coordination as fair or poor (OR 1.39 95% CI 1.03-1.86 p=0.03). Conclusions: Unmet needs are associated with high ES utilization in the first three years after cancer treatment. A better understanding of the reasons for this association is required to develop approaches to reduce potentially preventable ES utilization and improve perceived care needs among cancer survivors. [Table: see text]
Blockade of STAT3/IL-4 overcomes EGFR T790M-<i>cis</i>-L792F-induced resistance to osimertinib via promoting M2 macrophages polarization.
Authors: Yiting Sun, Yuanyuan Ma, Zhihua Tian, Xijuan Liu, Xiang Yan, Wei Zhao, Jie Wang, Zhijie Wang
Journal: Journal of Clinical Oncology (2022)

e20552 Background: Missense alteration at EGFR L792F emerges after osimertinib resistance in patients with non-small cell lung cancer (NSCLC). However, its mechanism has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation. Methods: Circulating tumor DNA-based sequencing data of 1382 patients with osimertinib resistance were collected to illustrate the prevalence of L792F mutation. Sensitivity to osimertinib was tested with constructed 19Del/T790M-cis-L792F mutations and control cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR 19Del/T790M-cis-L792F-induced osimertinib resistance were investigated. Also, possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored. Results: The concomitant EGFR L792 was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR L792F- cis mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutations. The upregulated phosphorylation of STAT3 Tyr705 and downstream expression and secretion of IL-4 induced M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed M2 macrophage polarization and regressed tumor sensitivity to osimertinib and delayed tumor growth. Conclusions: Our results provided solid evidence of EGFR T790M-cis-L792F mutation as a factor inducing osimertinib resistance. Targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC.
Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa
Authors: Sung-Ah Hong, Song-Ee Kim, A-Young Lee, Gue-Ho Hwang, Jong Hoon Kim, Hiroaki Iwata, Soo-Chan Kim, Sangsu Bae, Sang Eun Lee
Journal: Molecular Therapy (2022)

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.
Nucleobase-crosslinked poly(2-oxazoline) nanoparticles as paclitaxel carriers with enhanced stability and ultra-high drug loading capacity for breast cancer therapy
Authors: Si Dong, Sheng Ma, Hongyu Chen, Zhaohui Tang, Wantong Song, Mingxiao Deng
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Poly(2-oxazoline) (POx) has been regarded as a potential candidate for drug delivery carrier to meet the challenges of nanomedicine clinical translation, due to its excellent biocompatibility and self-assembly properties. The drug loading capacity and stability of amphiphilic POxs as drug nanocarriers, however, tend to be insufficient. Herein, we report a strategy to prepare nucleobase-crosslinked POx nanoparticles (NPs) with enhanced stability and ultra-high paclitaxel (PTX) loading capacity for breast cancer therapy. An amphiphilic amine-functionalized POx (PMBEOx-NH2) was firstly prepared through a click reaction between cysteamines and vinyl groups in poly(2-methyl-2-oxazoline)-block-poly (2‑butyl‑2-oxazoline-co-2-butenyl-2-oxazoline) (PMBEOx). Complementary nucleobase-pairs adenine (A) and uracil (U) were subsequently conjugated to PMBEOx-NH2 to give functional POxs (POxA and POxU), respectively. Due to the nucleobase interactions formed between A and U, NPs formed by POxA and POxU at a molar ratio of 1:1 displayed ultrahigh PTX loading capacity (38.2%, PTX/POxA@U), excellent stability, and reduced particle size compared to the uncross-linked PTX-loaded NPs (PTX/PMBEOx). Besides the prolonged blood circulation and enhanced tumor accumulation, the smaller PTX/POxA@U NPs also have better tumor penetration ability compared with PTX/PMBEOx, thus leading to a higher tumor suppression rate in two murine breast cancer models (E0711 and 4T1). These results proved that the therapeutic effect of chemotherapeutic drugs could be improved remarkably through a reasonable optimization of nanocarriers.
Even Low Amounts of Physical Activity Reduce Depression Risk
Authors: Anita Slomski
Journal: JAMA (2022)

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Value-based care outcomes in pancreatic cancer patients with and without access to registered dietitians: A retrospective cohort study of patients enrolled in the Oncology Care Model.
Authors: Karen Smith, Nicole Hodac, Terry Lynn Jensen, Vanessa Torres, Lance Ortega, Stephanie Broadnax Broussard, Holly Books, Kathryn Elizabeth Hudson, John Russell Hoverman, Lalan S. Wilfong
Journal: Journal of Clinical Oncology (2022)

e16249 Background: Patients with pancreatic cancer face many nutrition-related concerns, although few guidelines exist to direct clinical nutrition services in this population. Examining quality outcomes for patients in clinics with and without access to a Registered Dietitians (RD’s) can help examine the contributions of RD’s in this area. Methods: A retrospective cohort design was used to compare Total Cost of Care (TCOC), hospital admissions and Length of Stay (LOS), and Emergency Department (ED) and Observation visits for patients with pancreatic cancer who were enrolled in the Oncology Care Model (OCM) during Performance Periods (PP) 1-6 (July 1, 2016–June 30, 2019). Patient deaths during the initial episode of care were also examined. Patients from a geographically concentrated metropolitan hub were divided into cohorts based on clinic access to an RD. Each patient’s initial six-month OCM episode of care was used for analysis. Results: Of the 389 OCM patients identified with pancreatic cancer from PP1-6, 203 were treated at 10 clinics with an RD and 186 in 17 clinics without an RD. In the RD cohort, 43.3% of patients were admitted to the hospital with an average LOS of 8.9 days. By contrast, 52.2% of patients in the non-RD cohort were admitted to the hospital with an average LOS of 10.0 days. TCOC for the 6-month episode was lower in the RD cohort at $37,185 versus the non-RD cohort at $40,907. During the initial 6-month episode of care, 37% of patients in the non-RD cohort died during the initial 6-month episode vs only 28% in the RD cohort. A higher percentage of patients in the RD cohort (35%) had ED or Observation visits, compared with the non- RD cohort (32%). Conclusions: Amongst OCM patients with pancreatic cancers, treatment at a clinic with an RD was associated with lower TCOC, reduced LOS for patients that were admitted to the hospital, and lower percentage of deaths in the first 6-month episode of care. The percentage of patients with ED and Observational visits was slightly higher in the cohort that had access to an RD. This analysis shows the potential benefit of RD services in an outpatient setting and justifies further study. Future multilevel modeling will evaluate the statistical significance of these results.[Table: see text]
Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer
Authors: Miguel Lopez de Rodas, Venkata Nagineni, Arvind Ravi, Ila J Datar, Mari Mino-Kenudson, German Corredor, Cristian Barrera, Lindsey Behlman, David L Rimm, Roy S Herbst, Anant Madabhushi, Jonathan W Riess, Vamsidhar Velcheti, Matthew D Hellmann, Justin Gainor, Kurt A Schalper
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored. Methods We used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8 + cytotoxic T cells, CD4 + helper T cells and CD20 + B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao’s Q Index (RQI)). Results TILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8 + T cells were the most abundant subset. Higher density of stromal CD8 + cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort. Conclusion Baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC.
A phase I study of duvelisib in combination with oral azacitidine (CC-486) in relapsed lymphoid malignancies.
Authors: Hayder Saeed, Eva Sahakian, Kamira Karen Maharaj, Qianxing Mo, Ling Zhang, Rikesh J Makanji, Leidy Lismeri Isenalumhe, Sameh Gaballa, Julio C. Chavez, Bijal D. Shah, Celeste M. Bello, Javier Pinilla-Ibarz, Lubomir Sokol
Journal: Journal of Clinical Oncology (2022)

TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.
Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time?
Authors: Thomas A. Hope, Marianne Pavel, Emily K. Bergsland
Journal: Journal of Clinical Oncology (2022)

Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.